title: Synthesis, mechanistic studies, and anti-proliferative activity of glutathione/glutathione S-transferase-activated nitric oxide prodrugs.
abstract: Nitric oxide (NO) prodrugs such as O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K) are a growing class of promising NO-based therapeutics. Nitric oxide release from the anti-cancer lead compound, JS-K, is proposed to occur through a nucleophilic aromatic substitution by glutathione (GSH) catalyzed by glutathione S-transferase (GST) to form a diazeniumdiolate anion that spontaneously releases NO. In this study, a number of structural analogues of JS-K were synthesized and their chemical and biological properties were compared with those of JS-K. The homopiperazine analogue of JS-K showed anti-cancer activity that is comparable with that of JS-K but with a diminished reactivity towards both GSH and GSH/GST; both the aforementioned compounds displayed no cytotoxic activity towards normal renal epithelial cell line at concentrations where they significantly diminished the proliferation of a panel of renal cancer cell lines. These properties may prove advantageous in the further development of this class of nitric oxide prodrugs as cancer therapeutic agents.
authors.affiliation: Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD 21702, USA. chakrah@ncifcrf.gov
authors.forename: Harinath
authors.initials: H
authors.lastname: Chakrapani
authors.forename: Ravi C
authors.initials: RC
authors.lastname: Kalathur
authors.forename: Anna E
authors.initials: AE
authors.lastname: Maciag
authors.forename: Michael L
authors.initials: ML
authors.lastname: Citro
authors.forename: Xinhua
authors.initials: X
authors.lastname: Ji
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001391:Azo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D020030:Nitric Oxide Donors; C474958:O(2)-(2,4-dinitrophenyl) 1-((4-ethoxycarbonyl)piperazin-1-yl)diazen-1-ium-1,2-diolate; D010879:Piperazines; D011355:Prodrugs; C452539:diazeniumdiolate; D009569:Nitric Oxide; D005982:Glutathione Transferase; D005978:Glutathione